High-dose chemotherapy with autologous stem cell transplants has significantly improved the outcome of myeloma patients with normal metaphase cytogenetics; however, no such improvement has been observed in patients with abnormal cytogenetics (high-risk myeloma). Therefore, an entirely different approach is required for these patients. AIIogeneic donor T-cells can eradicate chemotherapy-resistant myeloma through a graft-versus-myeloma effect. Thus, based on these observations, we hypothesize that the outcome of high-risk myeloma can be improved upon by augmenting autotransplant therapy with immunologic manipulations, Three innovative treatment strategies will be explored in the Developmental Therapeutics Program: Aim 1 will evaluate the efficacy of a planned non-myeloablative allotransplant following a single autotransplant in patients with cytogenetic abnormalities. Aim 2 will evaluate whether improved EFS and OS can be obtained via vaccination with NY-ESO-1 or MAGE-A3 peptides prior to and after autotransplantation in previously treated patients expressing either of these genes in their myeloma cells. Aim 3 will evaluate whether the application of KIR-ligand-mismatched haploidentical donor natural killer (NK) cell infusions followed by an autotransplant can improve outcome in patients who have either relapsed after transplantation or have high risk myeloma. The major problem with non-myeloablative allotransplants (Aim 1) is the development of GVHD, which, although necessary to exert disease control, results in considerable morbidity and mortality. The other two approaches (Aims 2 and 3) try to accomplish a similar effective killing of myeloma cells without the development of GVHD. In each of these studies, EFS and OS will be compared to that of historical controls matched for the appropriate prognostic factors. Only those studies extending EFS byequal to or more than 30% at 24 months over that of historical controls will be considered worthwhile pursuing in a randomized study. Effective immunologic approaches, in combination with autotransplantation, should provide superior disease control in high-risk myeloma patients, and once superiority has been demonstrated, these strategies will be applied to standard-risk patients to further improve their outcome.